Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer

Abstract

Despite implementation of enhanced management practices, chronic wasting disease in US white-tailed deer (Odocoileus virginianus) continues to expand geographically. Herein, we perform the largest genome-wide association analysis to date for chronic wasting disease (n = 412 chronic wasting disease-positive; n = 758 chronic wasting disease-nondetect) using a custom Affymetrix Axiom single-nucleotide polymorphism array (n = 121,010 single-nucleotide polymorphisms), and confirm that differential susceptibility to chronic wasting disease is a highly heritable (h2= 0.611 ± 0.056) polygenic trait in farmed US white-tailed deer, but with greater trait complexity than previously appreciated. We also confirm PRNP codon 96 (G96S) as having the largest-effects on risk (P ≤ 3.19E-08; phenotypic variance explained ≥ 0.025) across 3 US regions (Northeast, Midwest, South). However, 20 chronic wasting disease-positive white-tailed deer possessing codon 96SS genotypes were also observed, including one that was lymph node and obex positive. Beyond PRNP, we also detected 23 significant single-nucleotide polymorphisms (P-value ≤ 5E-05) implicating ≥24 positional candidate genes; many of which have been directly implicated in Parkinson's, Alzheimer's and prion diseases. Genotype-by-environment interaction genome-wide association analysis revealed a single-nucleotide polymorphism in the lysosomal enzyme gene ARSB as having the most significant regional heterogeneity of effects on chronic wasting disease (P ≤ 3.20E-06); with increasing copy number of the minor allele increasing susceptibility to chronic wasting disease in the Northeast and Midwest; but with opposite effects in the South. In addition to ARSB, 38 significant genotype-by-environment single-nucleotide polymorphisms (P-value ≤ 5E-05) were also detected, thereby implicating ≥ 36 positional candidate genes; the majority of which have also been associated with aspects of Parkinson's, Alzheimer's, and prion diseases.

Keywords: PRNP; GWAA; GxE interaction; chronic wasting disease; white-tailed deer.

Fig. 1.

EMMAX binary case-control (0, 1) GWAA for CWD in farmed US white-tailed deer (Odocoileus virginianus; hereafter WTD). All dual-panel Manhattan plots depict −log10 P-values and the proportion of phenotypic variance explained (PVE) by white-tailed deer marker-effects on the y-axis, and the comparative position of all SNPs on the x-axis, as inferred by blastn alignment with the bovine genome (ARS-UCD1.2) (Seabury et al. 2020). All analyses include diagnostically confirmed CWD positive (n = 412) and CWD nondetect (n = 758) WTD. a) EMMAX GWAA for CWD with no fixed-effect covariates, high GRM heritability estimates ($h^2=\mathrm{ }0.611\mathrm{ }\pm \mathrm{ }0.056$) (Kang et al. 2010; Segura et al. 2012; Seabury et al. 2020), and relevant positional candidate genes. Genomic inflation factor (Pseudo-Lambda) = 1.007. b) EMMAX GxE GWAA for CWD with US WTD region of origin (Northeast, Midwest, South) as the environmental interaction term, and relevant positional candidate genes. Genomic inflation factor (Pseudo-Lambda) = 1.140.

Fig. 2.

Binary case-control (0, 1) meta-analysis for differential susceptibility to CWD in farmed US white-tailed deer (Odocoileus virginianus; hereafter WTD) from the Northeast, Midwest, and South. Individual EMMAX GWAA’s (Kang et al. 2010; Segura et al. 2012; Seabury et al. 2020) for each US region were used in conjunction with the METAL-based approach to conduct a meta-analysis (Willer et al. 2010). METAL-based analyses included diagnostically confirmed CWD positive (n = 412) and CWD nondetect (n = 758) WTD. a) METAL-based Z-score analysis of shared WTD SNP effects and positional candidate genes influencing differential susceptibility to CWD across 3 US regions (Northeast, Midwest, South). Genomic inflation factor (Pseudo-Lambda) = 1.015. b) METAL-based Cochran’s Q-test for heterogeneity of SNP effects (Cochran 1954; Willer et al. 2010) across 3 US regions (Northeast, Midwest, South) and relevant positional candidate genes. Genomic inflation factor (Pseudo-Lambda) = 0.997.